S Harmsen1, I Meijerman, J H Beijnen, J H M Schellens. 1. Department of Pharmaceutical Sciences, Division of Biomedical Analysis, Faculty of Science, Utrecht University, Utrecht, The Netherlands. s.harmsen@uu.nl
Abstract
PURPOSE: Induction of cytochrome P450 (CYP) 3A4, an enzyme that is involved in the biotransformation of more than 50% of all drugs, by xenobiotics is an important cause of pharmacokinetic drug-drug interactions in oncology. In addition to rifampicin and hyperforin, the anticancer drug paclitaxel has also been shown to be an inducer of CYP3A4 via activation of the pregnane X receptor (PXR). We therefore screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction. METHODS: A CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1'-hydroxylation of midazolam (a specific CYP3A4 probe) was determined. RESULTS: Paclitaxel, erlotinib, tamoxifen, ifosfamide, flutamide and docetaxel are able to activate PXR, while only strong PXR activation leads to significant induction of CYP3A4 activity. CONCLUSIONS: The identified PXR agonists may have the propensity to cause clinically relevant drug-drug interactions as a result of CYP3A4 induction.
PURPOSE: Induction of cytochrome P450 (CYP) 3A4, an enzyme that is involved in the biotransformation of more than 50% of all drugs, by xenobiotics is an important cause of pharmacokinetic drug-drug interactions in oncology. In addition to rifampicin and hyperforin, the anticancer drug paclitaxel has also been shown to be an inducer of CYP3A4 via activation of the pregnane X receptor (PXR). We therefore screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction. METHODS: A CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1'-hydroxylation of midazolam (a specific CYP3A4 probe) was determined. RESULTS:Paclitaxel, erlotinib, tamoxifen, ifosfamide, flutamide and docetaxel are able to activate PXR, while only strong PXR activation leads to significant induction of CYP3A4 activity. CONCLUSIONS: The identified PXR agonists may have the propensity to cause clinically relevant drug-drug interactions as a result of CYP3A4 induction.
Authors: Marian Y Williams-Brown; Sana M Salih; Xia Xu; Timothy D Veenstra; Muhammad Saeed; Shaleen K Theiler; Concepcion R Diaz-Arrastia; Salama A Salama Journal: J Steroid Biochem Mol Biol Date: 2011-05-10 Impact factor: 4.292
Authors: Carlota Oleaga; Anne Riu; Sandra Rothemund; Andrea Lavado; Christopher W McAleer; Christopher J Long; Keisha Persaud; Narasimhan Sriram Narasimhan; My Tran; Jeffry Roles; Carlos A Carmona-Moran; Trevor Sasserath; Daniel H Elbrecht; Lee Kumanchik; L Richard Bridges; Candace Martin; Mark T Schnepper; Gail Ekman; Max Jackson; Ying I Wang; Reine Note; Jessica Langer; Silvia Teissier; James J Hickman Journal: Biomaterials Date: 2018-08-04 Impact factor: 12.479
Authors: Bodine P S Belderbos; Koen G A M Hussaarts; Leonie J van Harten; Esther Oomen-de Hoop; Peter de Bruijn; Paul Hamberg; Robbert J van Alphen; Brigitte C M Haberkorn; Martijn P Lolkema; Ronald de Wit; Robert J van Soest; Ron H J Mathijssen Journal: Br J Clin Pharmacol Date: 2019-03-21 Impact factor: 4.335
Authors: Tasmin Reuter; Rolf Warta; Dirk Theile; Andreas D Meid; Juan Pablo Rigalli; Carolin Mogler; Esther Herpel; Niels Grabe; Bernd Lahrmann; Peter K Plinkert; Christel Herold-Mende; Gerhard Dyckhoff; Walter Emil Haefeli; Johanna Weiss Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2015-07-04 Impact factor: 3.000